This application is a 371 of PCT/JP99/07049, filed Dec. 15, 1999.
The present invention relates to a process for producing novel naphthyridine derivatives having an antagonistic action against tachykinin receptors, especially neurokinin A receptor (NK-2 receptor), intermediates used in this process, and a process for producing such intermediates.
The compounds acting antagonistically to various types of tachykinin receptors have been reported. For instance, JP-A-4-261155 discloses a compound having an antagonistic action against neurokinin receptors (especially NK-2 receptor). Further, JP-A-5-140103 describes a compound which antagonizes against substance P, neurokinin A or neurokinin B receptor. These compounds have a single ring containing a nitrogen atom, such as a piperidine ring, in the molecule, but no compound having a naphthyridine ring has ever been disclosed.
Regarding the compounds having a naphthyridine ring, JP-A-58-57379 discloses a compound having an anti-vertiginous action. However, it has never been reported that these compounds having a naphthyridine ring have an antagonistic action against tachykinin receptors.
The present invention is designed to provide a process for producing the novel naphthyridine derivatives showing a high activity as a tachykinin receptor antagonist, intermediates used in this process, and a process for producing such intermediates.
As a result of extensive studies on the subject matter, the present inventors found that the novel naphthyridine derivatives having a naphthyridine ring as the basic skeleton have a prominent antagonistic action against tachykinin receptors and are well applicable as pharmaceuticals. The present inventors have also pursued studies on the way of production of these derivatives and worked out a production process which can well withstand its industrial application. These findings underlie the present invention.
The novel naphthyridine derivatives of the present invention have the asymmetric carbon atoms, so that they exist as a single optically active compound or a racemate thereof, and each of them has an outstanding activity as a tachykinin receptor antagonist. Also, part of the novel naphthyridine derivatives of the present invention can be used as an intermediate for the synthesis of the other part of the naphthyridine derivatives of the present invention.
The optically active compounds comprising the novel naphthyridine derivatives of the present invention can be easily obtained as required by, for instance, optically resolving their intermediates. A diastereomer salt produced by acting an optically active amine to a racemate of the synthesis intermediate can be optically resolved by, for instance, a method making use of the difference in their physicochemical properties. Further, by using an isomeric crystallization method, it is possible to obtain an objective optically active product of the intermediate in a higher yield than obtainable with ordinary optical resolution. Using such optically active substances, it is possible to obtain the optically active compounds comprising the novel naphthyridine derivatives of the present invention at high efficiency.
The present invention has been achieved on the basis of the above findings.
Thus, the present invention provides:
(i) A process for producing a novel naphthyridine derivative, which comprises carrying out a condensation reaction between a compound represented by the following formula (1): 
wherein R1, R2 and R3 represent independently a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, a heteroaryl group, an amino group or a halogen atom, or R1 and R2 or R2 and R3 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group; and X1 and X2 represent respectively a halogen atom, and a compound represented by the following formula (2): 
wherein Y represents an aryl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group; and Z represents a halogen atom, a hydroxyl group, a lower alkylcarbonyloxy group or an arylcarbonyloxy group, to produce a compound represented by the following formula (3): 
wherein R1, R2, R3, X1, X2 and Y have the same meaning as defined above.
(ii) The process described in (i) above, wherein in the formula (1), R1 and R2 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom, aryl group, heteroaryl group and trifluoromethyl group; and R3 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, an amino group or a halogen atom.
(iii) The process described in (i) above, wherein in the formula (1), R1 and R2 are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group; R3 represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, an amino group or a halogen atom; and in the formula (2), Y represents a phenyl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group.
(iv) The process described in (i) above, wherein in the formula (1), R1 and R2 are combined to form a cyclic group with the interposition of a butylene group or a butenylene group; R3 represents a hydrogen atom, an aryl group, an amino group or a halogen atom; and in the formula (2), Y represents a phenyl group.
(v) A process for producing a novel naphthyridine derivative, which comprises acylating the amino group of a compound represented by the following formula (3)xe2x80x2: 
wherein R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 represent independently a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, a heteroaryl group, an amino group or a halogen atom, or R1xe2x80x2 and R2xe2x80x2 or R2xe2x80x2 and R3xe2x80x2 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group, and at least one of R1xe2x80x2, R2xe2x80x2 and R3xe2x80x2 is an amino group; X1 and X2 represent respectively a halogen atom; and Y represents an aryl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group, to produce a compound represented by the formula (3)xe2x80x3: 
wherein R1xe2x80x3, R2xe2x80x3 and R3xe2x80x3 represent independently a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, a heteroaryl group or a halogen atom, or R1xe2x80x3 and R2xe2x80x3 or R2xe2x80x3 and R3xe2x80x3 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group, and at least one of R1xe2x80x3, R2xe2x80x3 and R3xe2x80x3 is a lower alkylcarbonylamino group or an arylcarbonylamino group; and X1, X2 and Y have the same meaning as defined above.
(vi) The process described in (v) above, wherein in the formula (3)xe2x80x2, R1xe2x80x2 and R2xe2x80x2 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group; R3xe2x80x2 represents an amino group; and in the formula (3)xe2x80x3, R1xe2x80x3 and R2xe2x80x3 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group; and R3xe2x80x3 represents a lower alkylcarbonylamino group or an arylcarbonylamino group.
(vii) The process described in (v) above, wherein in the formula (3)xe2x80x2, R1xe2x80x2 and R2xe2x80x2 are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group; R3xe2x80x2 represents an amino group; Y represents a phenyl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group; and in the formula (3)xe2x80x3, R1xe2x80x3 and R2xe2x80x3 are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group; and R3xe2x80x3 represents a lower alkylcarbonylamino group.
(viii) The process described in (v) above, wherein in the formula (3)xe2x80x2, R1xe2x80x2 and R2xe2x80x2 are combined to form a cyclic group with the interposition of a butylene group or a butenylene group; R3xe2x80x2 represents an amino group; Y represents a phenyl group; and in the formula (3)xe2x80x3, R1xe2x80x3 and R2xe2x80x3 are combined to form a cyclic group with the interposition of a butylene group or a butenylene group; and R3xe2x80x3 represents a lower alkylcarbonylamino group.
(ix) Racemates, optical active products or salts of the 3-(3,4-dihalogenophenyl)propionic acid derivatives represented by the following formula (4): 
wherein X1 and X2 represent respectively a halogen atom; and R4 represents a C1-C20 hydrocarbon residue which may have a substituent and in which an oxygen, nitrogen or sulfur atom may exist.
(x) The compounds described in (ix) above, wherein X1 and X2 represent respectively a chlorine atom; and R4 represents a C1-C5 alkyl group which may be substituted with an aryl group.
(xi) The compounds described in (ix) or (x) above, which are the salts with an optically active amine.
(xii) The compounds described in (xi) above, wherein the optically active amine is 1-arylethylamine which may have a substituent.
(xiii) The compounds described in (xii) above, wherein the optically active amine is (S)- or (R)-1-phenylethylamine, (S)- or (R)-1-(p-tolyl)ethylamine, (s)- or (R)-1-(1-naphthyl)ethylamine, (S)- or (R)-1-phenyl-2-(p-tolyl)ethylamine or (S)- or (R)-N-benzyl-1-phenylethylamine.
(xiv) A process for producing an optically active 3-(3,4-dihalogenophenyl)propionic acid derivative, which comprises acting an optically active amine to a racemate of a 3-(3,4-dihalogenophenyl)propionic acid derivative represented by the formula (4): 
wherein X1 and X2 represent respectively a halogen atom; and R4 represents a C1-C20 hydrocarbon residue which may have a substituent and in which an oxygen, nitrogen or sulfur atom may exist, optically resolving the produced diastereomer salt, and decomposing the obtained optically active diastereomer salt.
(xv) The process described in (xix) above, wherein X1 and X2 represent respectively a chlorine atom; and R4 represents a C1-C5 alkyl group which may be substituted with an aryl group.
(xvi) The process described in (xiv) or (xv) above, wherein the optically active amine is 1-arylethylamine which may have a substituent.
(xvii) The process described in (xvi) above, wherein the optically active amine is (S)- or (R)-1-phenylethylamine, (S)- or (R)-1-(p-tolyl)ethylamine, (S)- or (R)-1-(1-naphthyl)ethylamine, (S)- or (R)-1-phenyl-2-(p-tolyl)ethylamine, or (S)- or (R)-N-benzyl-1-phenylethylamine.
(xviii) A process for producing a 3-(3,4-dihalogenophenyl)propionic acid derivative, which comprises carrying out an alkylation reaction with a compound epresented by the formula (5): 
wherein X1 and X2 represent respectively a halogen atom; and R4 represents a C1-C20 hydrocarbon residue which may have a substituent and in which an oxygen, nitrogen or sulfur atom may exist, to obtain a compound represented by the formula (4): 
wherein X1 and X2 represent respectively a halogen atom; and R4 represents a C1-C20 hydrocarbon residue which may have a substituent and in which an oxygen, nitrogen or sulfur atom may exist.
(xix) The process described in (xviii) above, wherein the compound is treated with an alkaline metal halogenoacetate in an aprotic polar solvent in the presence of a strong base at a temperature from xe2x88x9240xc2x0 C. to +25xc2x0 C.
(xx) A process for producing an amine compound, which comprises reacting a compound represented by the formula (6): 
wherein A represents a benzene ring which may have a substitutent selected from lower alkyl group, lower alkoxyl group, aryl group, heteroaryl group, amino group, halogen atom and trifluoromethyl group, with a compound represented by the formula (7): 
wherein R5 represents a methyl group which may be substituted with a lower alkyl group or an aryl group in the presence of a reacting agent represented by the formula (8): 
wherein R6, R7 and R8 represent independently a lower alkyl group or an aryl group; and Z represents a halogen atom or a fluorinated alkyl sulfonate, to produce a compound represented by the formula (9): 
wherein A and R5 are as defined above.
(xxi) The process described in (xx) above, wherein in the formula (6), A represents a benzene ring substituted with a hydrogen atom, a halogen atom or a lower alkyl group; in the formula (7), R5 represents a methyl group or a benzyl group; and in the formula (8), R6, R7 and R8 represent independently a methyl group, an ethyl group, an isopropyl group, a tert-butyl group or a phenyl group, and Z represents bromine, iodine, trifluoromethane sulfonate, pentafluoroethane sulfonate, pentafluoro-n-propane sulfonate or nanofluoro-n-butane sulfonate.
(xxii) The process described in (xxi) above, wherein in the formula (6), A represents a non-substituted benzene ring; in the formula (7), R5 represents a benzyl group; and in the formula (8), R6, R7 and R8 represent a methyl group, and Z represents bromine, iodine or trifluoromethane sulfonate.
In the naphthyridine derivatives according to the present invention, the lower alkyl group is preferably a C1-C4 linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Of these groups, methyl and ethyl are preferred.
The lower alkoxyl group in the derivatives of the present invention is preferably a C1-C4 linear or branched alkoxyl group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Of these groups, methoxy and ethoxy are preferred.
The halogen atom in the derivatives of the present invention is fluorine atom, chlorine atom, bromine atom or iodine atom, of which chlorine atom is preferred.
The aryl group in the derivatives of the present invention is preferably a C6-C14 aryl group such as phenyl, biphenyl, naphthyl, anthryl and phenanthryl, of which phenyl and. naphthyl are preferred.
The heteroaryl group in the derivatives of the present invention is preferably an unsaturated 5- to 7-member ring containing 1 to 5, preferably 1 to 2 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom, such as thienyl, imidazolyl, pyridinyl, pyridiminyl and pyridazinyl.
The C2-C5 alkylene group in the derivatives of the present invention is, for instance, ethylene, propylene, butylene or pentylene.
The C2-C5 alkenylene group in the derivatives of the present invention is, for instance, ethynylene, propenylene, butynylene or pentenylene.
The lower alkylcarbonyloxy group in the derivatives of the present invention is a group comprising a lower alkyl group such as mentioned above to which a carbonyloxy group is attached.
The arylcarboxyloxy group in the derivatives of the present invention is a group comprising an aryl group such as mentioned above to which a carbonyloxy group is attached.
The hydrocarbon residue in the derivatives of the present invention is preferably a C2-C5 alkylene group, a C2-C5 alkenylene group, a C6-C14 aryl group, such as mentioned above, or the like.
In the formulae (1) and (3), preferably R1 and R2 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond. This cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, lower alkoxyl group, aryl group, heteroaryl group, halogen atom and trifluoromethyl group. R3 in these formulae is preferably a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, an amino group or a halogen atom. More preferably, R1 and R2 are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent such as mentioned above. Most preferably, R1 and R2 are combined to form a cyclic group with the interposition of a butylene or butenylene group, and R3 is a hydrogen atom, an aryl group, an amino group or a halogen atom.
In the formula (3)xe2x80x2, preferably R1xe2x80x2 and R2xe2x80x2 are combined to form a cyclic group which may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom, with the interposition of a saturated or unsaturated carbon-carbon bond. This cyclic group may also have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group. R3xe2x80x2 is preferably an amino group. More preferably, R1xe2x80x2 and R2xe2x80x2 are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group. Most preferably, R1xe2x80x2 and R2xe2x80x2 are combined to form a cyclic group with the interposition of a butylene or butenylene group.
In the formula (3)xe2x80x3, R1xe2x80x3 and R2xe2x80x3 are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, lower alkoxyl group, aryl group, heteroaryl group, halogen atom and trifluoromethyl group. R3xe2x80x3 is preferably a lower alkylcarbonylamino group or an arylcarbonylamino group. More preferably, R1xe2x80x3 and R2xe2x80x3 are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group. R3xe2x80x3 is preferably a lower alkylcarbonylamino group. Most preferably, R1xe2x80x3 and R2xe2x80x3 are combined to form a cyclic group with the interposition of a butylene or butenylene group, and R3xe2x80x3 is a lower alkylcarbonylamino group.
The hydrocarbon residue represented by R4 in the formulae (4) and (5) is the one whose carbon number is preferably from 1 to 10, more preferably from 1 to 5. The substituents of this hydrocarbon residue include C1-C5 alkoxyl group, nitro group, halogen and aryl group, preferably C1-C5 alkoxyl group. Preferred examples of R4 are methyl, ethyl, propyl, butyl and benzyl. Practically, methyl, ethyl and benzyl are preferred.
In the formulae (2), (3) and (3)xe2x80x2, preferably Y is a phenyl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group, more preferably a phenyl group.
In the formulae (6) and (9), A represents a benzene ring whose substituent is selected from lower alkyl group, lower alkoxyl group, aryl group, heteroaryl group and halogen atom, the examples of which are the same as mentioned above. The preferred substituents are halogen atom and lower alkyl group. Most preferably, A is a non-substituted benzene ring.
In the formula (7), R5 is preferably a methyl group substituted with an aryl group, most preferably a benzyl group.
In the formula (8), preferably R6, R7 and R8 are a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a phenyl group or the like, and most preferably, all of R6, R7 and R8 are a methyl group.
The halogen atoms represented by Z in the formula (8) are the same as mentioned above. The fluorinated alkyl sulfonates also represented by Z include, for example, trifluoromethane sulfonate, pentafluoroethane sulfonate, heptafluoromethane sulfonate and nanofluoro-n-butane sulfonate. Z is preferably a bromine atom, an iodine atom or trifluoromethane sulfonate.
The compounds represented by the formula (3) include the following:
{circle around (1)}-a: (xc2x1)-10-amino-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (1)}-b: (xe2x88x92)-10-amino-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (1)}-c: (+)-10-amino-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (2)}-a: (xc2x1)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (2)}-b: (xe2x88x92)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (2)}-c: (+)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (3)}-a: (xc2x1)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichorophenyl)butyl]-10-phenyl-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (3)}-b: (xe2x88x92)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dihclorophenyl)butyl]-10-phenyl-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (3)}-c: (+)-2-[4-(N-benzoyl-N-naphthyl)amino-3-(3,4-dichlorophenyl)butyl]-10-phenyl-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (4)}-a: (xc2x1)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (4)}-b: (xe2x88x92)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (4)}-c: (+)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine.
The compounds represented by the formula (3)xe2x80x3 include the following:
{circle around (5)}-a: (xc2x1)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (5)}-b: (xe2x88x92)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (5)}-c: (+)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
{circle around (6)}-a: (xc2x1)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (6)}-b: (xe2x88x92)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (6)}-c: (+)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (7)}-a: (xc2x1)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-difluorophenyl)butyl]-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (7)}-b: (xe2x88x92)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-difluorophenyl)butyl]-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (7)}-c: (+)-10-acetylamino-2-[4-(N-benzoyl-N-methyl)-amino-3-(3,4-difluorophenyl)butyl]-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (8)}-a: (xc2x1)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-difluorophenyl)butyl]-10-benzoylamino-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
{circle around (8)}-b: (xe2x88x92)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-difluorophenyl)butyl]-10-benzoylamino-1,2,3,4-tetrahydrobenzo[b][1.6]-naphthyridine;
{circle around (8)}-c: (+)-2-[4-(N-benzoyl-N-methyl)amino-3-(3,4-difluorophenyl)butyl]-10-benzoylamino-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine.
The novel naphthyridine derivatives produced according to the present invention may be used in the form of pharmacologically acceptable salts. Such salts, to be concrete, include the salts with mineral acids such as hydrochloric acid and sulfuric acid, and the salts with organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid.
The production processes according to the present invention are described in detail below.
The novel naphthyridine derivatives of the formulae (3) and (3)xe2x80x3 of the present invention can be produced according to the conventional synthesis processes illustrated by the following schemes 1 and 2. 
In Scheme 1, the compound represented by the formula (5) can be obtained by reacting a compound of the formula (10), which is easily available from, for example, Tokyo Kasei KK (Tokyo), with a halogenated hydrocarbon compound such as alkyl halide or benzyl halide in a solvent such as an alcohol (methanol, ethanol, etc.), acetone or dimethylformamide in the presence of a basic catalyst such as potassium carbonate, potassium hydroxide or sodium hydroxide under the range of room temperature to solvent-reflux temperature. It is also possible to obtain the compound of the formula (5) by reacting a compound of the formula (10) with a corresponding alcohol compound (R4OH) in a non-alcoholic organic solvent in the presence of an acid catalyst such as sulfuric acid or hydrochloric acid under reflux by heating from room temperature.
The compound of the formula (4) can be obtained by alkylating the compound of the formula (5) with an alkaline metal halogenoacetate in an aprotic polar solvent in the presence of a strong base.
As the aprotic polar solvent, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and the like can be used, but dimethylformamide and dimethyl sulfoxide are preferred, the latter being especially preferred.
As the strong base, sodium hydroxide, sodium tert-butoxide, n-butyllithium, lithium, diisopropylamide, etc., can be used, of which sodium hydroxide and sodium tert-butoxide are preferred, the former being particularly preferred.
As the alkaline metal halogenoacetate, sodium chloroacetate, potassium bromoacetate, etc., can be used, with sodium chlorocetate being preferred.
The reaction can be carried out in a wide temperature range of from xe2x88x9278xc2x0 C. to 100xc2x0 C., but practically a temperature from xe2x88x9240xc2x0 C. to 25xc2x0 C. is preferably used.
The compound of the formula (4) obtained in the manner described above can be optically resolved as required in the following way.
An optically active amine and a solvent, preferably an isomerization assistant, are added to a (xc2x1)-3-(3,4-dihalogenophenyl)propionic acid derivative of the formula (4), and with the amount of the solvent adjusted to allow crystallization of the best part of the diastereomer which is less soluble in said solvent, the mixture is stirred by heating at a temperature of from 50xc2x0 C. to around the boiling point of the solvent used, preferably at 60xc2x0 C. to 120xc2x0 C., for several to several ten hours, accumulating the diastereomer salt which is lower in solvent solubility in the two types of diastereomer salt, then the accumulated diastereomer salt is cooled to xe2x88x9210 to 40xc2x0 C. and the precipitated hardly soluble salt is separated.
As the optically active amine, it is possible to use any type which is capable of forming a crystallizable salt with the 3-(3,4-dihalogenophenyl)propionic acid derivative of the formula (4). Usually, an easily available basic optical resolving agent is used. In this case, those which are easily racemated with an isomerization assistant described later should be avoided. Examples of the optically active amines usable in the present invention include, as those of the natural origin, quinine, quinidine, cinchonine, cinchonidine, ephedrine, L-lysine, (+)-dehydroabiethylamine and L-alginine. The synthetic products of such optically active amines include (+)- or (xe2x88x92)-1-phenylethylamine, (+)- or (xe2x88x92)-1-(p-tolyl)ethylamine, (+)- or (xe2x88x92)-1-(o-tolyl)ethylamine, (+)- or (xe2x88x92)-1-(m-tolyl)ethylamine, (+)- or (xe2x88x92)-1-(p-nitrophenyl)ethylamine, (+)- or (xe2x88x92)-1-(p-isopropylphenyl)ethylamine, (+)- or (xe2x88x92)-xcex1-ethylbenzylamine, (+)- or (xe2x88x92)-1-(p-chlorophenyl)ethylamine, (+)- or (xe2x88x92)-1-(p-methoxyphenyl)ethylamine, (+)- or (xe2x88x92)-1-(p-nitrophenyl)ethylamine, (+)- or (xe2x88x92)-1-phenyl-2-(p-tolyl)ethylamine, (+)- or (xe2x88x92)-erythro-2-amino-1,2-diphenylethanol, (+)- or (xe2x88x92)-1-(1-naphtyl)ethylamine, (+)- or (xe2x88x92)-1-(2-naphthyl)ethylamine, (+)- or (xe2x88x92)-cis-2-(benzylamino)cyclohexanemethanol, (+)- or (xe2x88x92)-xcex1-methyl-p-nitrobenzylamine, (+)- or (xe2x88x92)-N-benzyl-1-phenylethylamine, and (+)- or (xe2x88x92)-N-(p-nitrobenzyl)-1-phenylethylamine. The optionally substituted (+)- or (xe2x88x92)-xcex1-arylethylamine derivatives are preferably used, with (+)- or (xe2x88x92)-1-phenylethylamine being particularly preferred.
As the solvent, there can usually be used alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, di-n-propyl ketone, di-iso-propyl ketone and methyl isopropyl ketone; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane, isopropyl ether, 2-methoxyethyl ether and diethyl ether; hydrocarbons such as hexane, heptane and octane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; esters such as methyl acetate, ethyl acetate and butyl acetate; nitrites such as acetonitrile and propionitrile; water, and suitable combinations of these solvents. Alcohols such as ethanol, 1-propanol, 2-propanol and 1-butanol are preferably used. The amount of the solvent to be used is variable depending on the type of the solvent, the (xc2x1)-3-(3,4-dihalogenophenyl)propionic acid derivative and the optically active amine used, but usually an amount is selected that will cause crystallization of the most part of the diastereomer which is less soluble in the solvent. It is approximately 1 to 200 ml, preferably about 2 to 80 ml, per 1 g of the diastereomer salt.
As the isomerization assistant, the amines having stronger basicity than the optically active amine used as the optical resolving agent can be used. Examples of such amines include organic bases such as 1,8-diazabicyclo[5.4.0]undeca-7-en (DBU), 1,5-diazabicyclo[4.3.0]nonane-5-en (DBN), 6-dibutylamino1,8-diazabicyclo[5.4.0]undeca-7-en, and 1,4-diazabicyclo[2.2.2]octane (DABCO); alkali metal alkoxides such as potassium t-butoxide and sodium methoxide; and tertiary amines such as triethylamine, tri-n-butylamine, N,N-dimethylaminocyclohexylamine, and N,N,Nxe2x80x2,Nxe2x80x2-tetramethylenediamine. DBU, DBN and DABCO are preferred. Such an isomerization assistant is usually used in an amount of approximately 0.01 to 0.3 mole, preferably approximately 0.02 to 0.2 mole, per 1 mole of the diastereomer salt.
The molar ratio of the optically active amine used as the resolving agent to the (xc2x1)-3-(3,4-dihalogenophenyl)propionic acid derivative is preferably 0.8-1.2 in view of resolving efficiency. It is also possible to prepare the optically active 3-(3,4-dihalogenophenyl)propionic acid derivatives differing in optical rotation according to the difference in optical rotation of the optically active amines. For instance, in case of using (xc2x1)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid while using 2-propanol as solvent, there can be obtained (+)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid when using (xe2x88x92)-1-phenylethylamine as optically active amine, and (xe2x88x92)-3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid can be obtained when using (+)-1-phenylethylamine.
The crystals of the thus obtained diastereomer salt may, if necessary, be recrystallized and then decomposed by acting a mineral acid such as hydrochloric acid or sulfuric acid, and the freed optically active 3-(3,4-dihalogenophenyl)propionic acid derivative may be extracted with an organic solvent such as ethyl acetate, ether, chloroform or toluene to obtain the objective product with high purity.
By using the thus obtained optically active products of the compounds of the formula (4), it is possible to obtain the novel naphthyridine derivatives represented by the formulae (3) and (3)xe2x80x3 as the optically active compounds.
The following can be cited as examples of the compounds represented by the formula (4). All of them comprehend racemates and optically active products.
3-(3,4-dichlorophenyl)-3-methoxycarbonylpropionic acid;
3-(3,4-dichlorophenyl)-3-ethoxycarbonylpropionic acid;
3-(3,4-dichlorophenyl)-3-benzyloxycarbonylpropionic acid;
3-(3,4-difluorophenyl)-3-methoxyethoxycarbonylpropionic acid.
A condensation reaction of a compound of the formula (4) with an amine compound of the formula (11) gives a compound represented by the formula (12). Such a condensation reaction can be effected by first activating a carboxylic acid of the formula (4) as an active ester, acid halide or mixed acid anhydride, and then condensing therewith an amine compound of the formula (11). For instance, the objective condensation can be accomplished by reacting a compound of the formula (4) with thionyl chloride, oxalyl chloride or the like in an aprotic solvent such as toluene, dichloroethane or tetrahydrofuan to form an acid chloride, or reacting a compound (4) with ethyl chloroformate, acetic anhydride or the like in an aprotic solvent such as mentioned above to activate the said compound as a mixed acid anhydride, and then supplying an amine compound of the formula (11) into the reaction solution.
Such condensation can also be effected by using a condensing agent such as, for example, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-3-dimethylaminopropylcarbodiimde, diphenylphosphoryl azide, propanesulfonic acid anhydride trimer (T3P) or the like. As the reaction acceletator, N-hydroxysuccinimide, 1-hydroxybenzotriazole or the like can be used. As for the reaction solvent and the reaction conditions, those commonly used for the peptide syntheses can be employed.
The amine compounds of the formula (11) can be produced by, for example, the methods described in JP-A-58-057379, J. Heterocyclic Chem., 33, 1807 (1996), JP-A-3-2166, J. Chem. Soc., 708 (1964), J. Org. Chem, 2899 (1966), and J. Med. Chem., 32, 1295 (1989).
In the present invention, a process for producing the amine compounds of the formula (9) according to the method (xx) described above was discovered.
The compounds of the formulae (6), (7) and (8) in the method (xx) described above are mostly commercially available. For example, 2-aminobenzonitrile, N-benzylpiperidine-4-one and trimethylsilyltrifluoromethane sulfonate, which are the representative compounds of the formulae (6), (7) and (8), respectively, can be procured from Tokyo Kasei KK as reagents. Other compounds are also similarly available. Further, it is possible to produce them from a less costly material if so desired. For example, the compounds of the formula (8) wherein Y is a fluorinated alkyl sulfonate can be easily produced by the method shown in Synthesis, page 1, 1982.
Examples of the compounds represented by the formula (6) are:
2-aminobenzonitrie;
2-amino-6-methylbenzonitrile;
2-amino-6-fluorobenzonitrile;
2-amino-5-fluorobenzonitrile; and
2-amino-5-chlorobenzonitrile.
Examples of the compounds represented by the formula (7) are:
N-benzylpiperidine-4-one; and
N-methylpiperidine-4-one.
Examples of the compounds represented by the formula (8) are:
trimethylsilyltrifluoromethane sulfonate;
tert-butyldimethylsilyltrifluoromethane sulfonate;
tert-butyldiphenylsilyltrifluoromethane sulfonate;
triisopropylsilyltrifluoromethane sulfonate;
triethylsilyltrifluoromethane sulfonate;
trimethylsilylnonafluoro-n-butane sulfonate;
trimethylsilane iodide;
trimethylsilane bromide; and
trimethylsilane chloride.
A process for producing an amine compound of the formula (9) is described below.
A compound of the formula (6) and a compound of the formula (7) are used in such a ratio that the amount of the compound (7) will fall within the range of 0.1 to 10 equivalents, preferably 0.7 to 3 equivalents, to one equivalent of the compound (6). The compound (6)/compound (8) ratio is such that the amount of the compound (8) will fall within the range of 0.05 to 10 equivalents, preferably 0.2 to 5 equivalents, to one equivalent of the compound (6).
As the reaction solvent, it is possible to use any type as far as it is capable of allowing the reaction to proceed, but an aprotic solvent is preferred. The aprotic solvents usable for the reaction include aromatic hydrocarbon solvents such as toluene and benzene; aliphatic hydrocarbon solvents such a hexane and pentane; ester type solvents such as ethyl acetate and methyl acetate; halogenated hydrocarbon solvents such as chloroform and methylene chloride; ether type solvents such as diethyl ether, tetrahydrofuran and diisopropyl ether; aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide; and mixtures of these solvents. Of these solvents, the aromatic hydrocarbon solvents such as toluene and benzene, and ester type solvents such as ethyl acetate and methyl acetate are preferred.
The reaction can be carried out in a wide temperature range of from xe2x88x9278xc2x0 C. to the temperature at which the solvent can be refluxed, preferably from room temperature to the solvent-refluxed temperature. The reaction time is not specifically defined; the reaction is allowed to continue until it is completed. The reaction product obtained according to the process of the present invention may be filtered or extracted with water to provide it as a salt, for example, as a sulfonate, iodide or bromide. Further, a base may be acted to the obtained salt to render it into a free form, the latter being subjected to an ordinary purification means such as extraction with an organic solvent, chromatography, distillation, crystallization, suspension purification, etc., to obtain an amine compound of the formula (9).
The compounds of the formula (9), where R5 is a benzyl group, can be easily led into the corresponding amine compounds of the formula (11) by a hydrogenation reducing reaction. As the catalyst for this reaction, palladium or platinum type catalysts can be used. As the solvent, alcohol or ether type solvents, water, acetic acid, trifluoroacetic acid and the like can be used. The reaction is carried out at a temperature of from xe2x88x9220xc2x0 C. to 200xc2x0 C., under a pressure of from normal pressure to 100 atm for a period of from 5 minutes to 48 hours. As the hydrogen source, hydrogen gas, 1,4-cyclohexadiene, formic acid and the like can be used.
Examples of the amine compounds represented by the formula (11) are:
1,2,3,4,6,7,8,9-octahydro-benzo[b][1,6]-naphthyridine;
10-chloro-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine;
10-amino-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine; and
10-phenyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine.
Further, by hydrolyzing the compounds of the formula (12) in a solvent, for example, an alcohol such as methanol or ethanol, an ether such a tetrahydrofuran or 1,4-dioxane, water, or a mixture thereof, in the presence of a basic catalyst such as sodium hydroxide or potassium carbonate or an acid catalyst such as p-toluenesulfonic acid, there can be obtained the compounds represented by the formula (13).
When R4 in the compounds of the formula (12) is a benzyl group, it is possible to obtain the compounds of the formula (13) by subjecting the compounds (12) to a hydrogenation reduction reaction using a palladium type or platinum type catalyst. As the solvent, the alcohol type or ether type, water, etc., can be used. The reaction is carried out at a temperature of from xe2x88x9220xc2x0 C. to 100xc2x0 C. for a period of from 5 minutes to 48 hours. As the hydrogen source, hydrogen gas, 1,4-cyclohexadiene, formic acid and the like can be used.
By reacting the compounds of the formula (13) with thionyl chloride, oxalyl chloride or the like in an aprotic solvent such as toluene, dichloromethane or tetrahydrofuran to form an acid chloride, or reacting the said compounds with chloroethyl formate, acetic anhydride or the like in an aprotic solvent such as mentioned above to form a mixed acid anhydride, activating this reaction product and further subjecting it to a condensation reaction with methylamine, the compounds of the formula (14) can be obtained.
Condensation can be effected by using a condensing agent. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-3-dimethylaminopropylcarbodiimide, diphenylphosphorylazide, propanesulfonic anhydride trimer (T3P) and the like can be used. As the reaction accelerator, N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like can be used. The reaction solvent and the reaction conditions may be the same as those used for the ordinary peptide syntheses.
The compounds of the formula (14) can be transformed into the compounds of the formula (1) by subjecting the compounds (14) to a reduction reaction under the range of xe2x88x9220xc2x0 C. to solvent-reflux temperature, using a strong reducing agent such as diborane or alkylborane including dimethylborane sulfide, lithium aluminum hydride, diisobutyl aluminum hydride or aluminum hydride in an aprotic solvent such as dichloromethane, tetrahydrofuran or diethyl ether. Diborane or a borane-ligand complex is preferably used. For example, the objective reductants, or the compounds of the formula (1), can be obtained by a method using a borane-tetrahydrofuran complex which is available from Aldrich, etc., or a method in which sodium boron hydride and a boron trifluoride-ether complex are acted to produce diborane or a borane-ligand complex in the reactor.
Examples of the compounds represented by the formula (1) are shown below. All of these compounds include the racemates and the optically active version.
2-[4-(N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydro-benzo[b][1,6]-naphthyridine;
10-amino-2-[4-(N-methyl)amino-3-(3,4-difluorophenyl)butyl]-1,2,3,4,6,7,8,9-octahydrobenzo[b][1,6]-naphthyridine;
2-[4-(N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-10-phenyl-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine;
10-amino-2-[4-(N-methyl)amino-3-(3,4-dichlorophenyl)butyl]-7-trifluoromethyl-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine.
The compounds of the formula (1) can be converted into the novel naphthyridine derivatives of the formula (3) by subjecting the compounds (1) to a condensation reaction with a carboxylic acid of the formula (2) or a derivative thereof. Condensation can be effected by a method using a commercially available acylating agent as the carboxylic acid derivative of the formula (2). As the acylating agent, acid anhydrides such as benzoic anhydride, acid halides such as benzoyl chloride and p-anisoyl chloride, diketenes and the like can be used. Acid anhydrides or acid chlorides are preferred.
It is also possible to employ a process in which a carboxylic acid of the formula (2) is activated as an active ester, acid halide or mixed acid anhydride, and successively a compound of the formula (1) is condensed therewith. In this case, for instance, the following methods can be used: the compound (1) is reacted with thionyl chloride or oxalyl chloride in an aprotic solvent such as toluene, dichloromethane or tetrahydrofuran to form an acid halide; the compound (1) is reacted with chloroethyl formate, acetic anhydride or the like in an aprotic solvent such as mentioned above to form a mixed acid anhydride and this product is activated; or the compound (1) is reacted with 1,1xe2x80x2-carbonyldiimidazole or the like in an aprotic solvent such as mentioned above and thereby activated.
It is also possible to carry out the condensation reaction of a compound of the formula (1) with a carboxylic acid of the formula (2) by using a condensing agent. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-3-dimethylaminopropylcarbodiimde, diphenylphosphoryl azide, propanesulfonic anhydride trimer (T3P) and the like can be used. As the reaction accelerator, N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like can be used.
As the reaction solvent, there can be used halogen type solvents such as dichloromethane and chloroform, aprotic polar solvents such as dimethylformamide and 1,3-dimethyl-2-imidazolidinone, ethers such as tetrahydrofuran and dioxane, water, and mixtures thereof.
The reaction can be conducted in a temperature range of from xe2x88x9278xc2x0 C. to around the boiling point of the solvent used, preferably from xe2x88x9230xc2x0 C. to 50xc2x0 C., more practically from xe2x88x9220xc2x0 C. to 40xc2x0 C.
As shown in Scheme 2, the novel naphthyridine derivatives represented by the formula (3)xe2x80x3, which are part of the novel naphthyridine derivatives of the present invention, can be obtained by acylating the amino group of the novel naphthyridine derivatives represented by the formula (3)xe2x80x2.
As the acylating agent, acid anhydrides such as acetic anhydride and propionic anhydride, acid halides such as benzoyl chloride and p-anisoyl chloride, diketene, and the like can be used, but acid anhydrides are preferred. If necessary, an acid catalyst may be introduced. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid and the like can be used, with phophoric acid being preferred.
A reaction solvent may or may not be used. The solvents usable for the reaction include halogen type solvents such as dichloromethane and chloroform; aprotic polar solvents such as dimethylformamide, diglyme (diethylene glycol dimethyl ether) and 1-methyl-2-pyrrolidinone; ethers such as tetrahydrofuran and dioxane; basic solvents such as triethylamine and pyridine; and mixtures of these solvents. Aprotic polar solvents such as 1-methyl-2-pyrrolidinone or basic solvents such as triethylamine and pyridine are preferably used.
The reaction can be carried out in a temperature range of from xe2x88x9240xc2x0 C. to around the boiling point of the solvent used, preferably from 0xc2x0 C. to around the boiling point of the solvent, more preferably from 60xc2x0 C. to 130xc2x0 C.
The novel naphthyridine derivatives of the present invention represented by the formulae (3) and (3)xe2x80x3 can be produced according to a conventional synthesis process shown as Scheme 3 below. 
In Scheme 3, 4-amino-3-(3,4-dihalogeno-substituted phenyl)butyric acid of the formula (15) used as the starting material can be produced by, for example, the method described in Acta Pharmaceutical Sinica 1990; 25(1) : 11-17.
An optically active compound of the formula (15) can be obtained by, for example, the method disclosed in JP-A-3-206086, so that by using such an optically active compound as the starting material, it is possible to obtain a novel naphthyridine derivative of the present invention represented by the formula (3) or (3)xe2x80x3 as an optically active compound.
The compound of the formula (15) is subjected to a condensation reaction with an acid chloride such as chloroethyl formate or an acid anhydride such as di-tert-butyl-dicarbonate in a solvent such as dichloromethane, tetrahydrofuran, 1,4-dioxane, water or a mixture thereof to provide a compound represented by the formula (16).
This compound of the formula (16) is further reacted with thionyl chloride, oxalyl chloride or the like in an aprotic solvent such as toluene, dichloromethane or tetrahydrofuran to form an acid chloride, or reacted with chloroethyl formate, acetic anhydride or the like in an aprotic solvent such as mentioned above to form a mixed acid anhydride, and this product is activated and subjected to a condensation reaction with an amine compound of the formula (11) to give a compound of the formula (17).
This formula (17) compound can be turned into a compound of the formula (1) by subjecting the formula (17) compound to a reduction reaction under reflux at a temperature of from xe2x88x9220xc2x0 C. to a heating temperature in an aprotic solvent such as dichloromethane, tetrahydrofuran or diethyl ether by using a strong reducing agent such as diborane containing dimethylborane sulfide, lithium aluminum hydride or diisobutyl aluminum hydride.
Following thereafter the same procedure as described above, it is possible to produce a novel naphthyridine derivative of the present invention represented by the formula (3) or (3)xe2x80x3.
In use of the novel naphthyridine derivatives of the present invention represented by the formulae (3) and (3)xe2x80x3 as a tachykinin receptor antagonist, they are worked into various forms of preparation such as suspension, emulsion, injection, inhalant, tablet, pill, granule, powder, capsule, peroral liquid, supposition, eye drops, eye ointment, percutaneous liquid, ointment, permucous attachment, spray, etc., either independently or after being mixed with an appropriate excipient or carrier, and administered perorally or parenterally.
The adjuvants used as excipient or carrier are the pharmacologically acceptable ones, and their type and composition are decided depending on the course and way of administration. For instance, in the case of injections, starch, lactose, crystal cellulose, magnesium stearate or the like is preferably selected as adjuvant. Other ordinarily used adjuvants such as auxiliary agent, stabilizer, wetting agent, emulsifier, buffer, etc., may be contained as desired in the above preparations.
The content of the novel naphthyridine derivative in the preparations, though variable depending on the type of the preparation, is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of injection, it is prepared so that a novel naphthyridine derivative will be contained in an amount of usually 0.1 to 30% by weight, preferably 1 to 10% by weight. In the case of peroral preparations, they are used in the form of tablet, capsule, powder, granule, liquid, dry syrup or the like with the adjuvants. Such a tablet, capsule, powder and granule contains usually 5 to 100% by weight, preferably 25 to 98% by weight of a novel naphthyridine derivative.
Dosage is decided by taking into consideration the patient""s age, sex, body weight, condition, therapeutical purpose and other factors, but it is usually 0.001 to 100 mg/kg/day for parenteral administration and 0.01 to 500 mg/kg/day for peroral administration, and this dosage may be given either all at one time or in two to four portions.